This invention relates to pharmaceutical dosage forms for the treatment of gastric disorders, and more particularly to multiple layer or multiple portion solid oral dosage forms comprising a histamine H2-receptor antagonist and an antacid.
Gastrointestinal disorders such as acid indigestion, heartburn and gastritis are commonly treated with a histamine H2-receptor antagonist such as cimetidine, ranitidine, nizetidine and famotidine. Histamine H2-receptor antagonists reduce acid secretion by acting directly on the acid-secreting parietal cells located within the gastric gland of the stomach wall.
Antacids such as sodium bicarbonate, calcium carbonate, aluminum hydroxide and magnesium hydroxide are also commonly employed in the treatment of a large variety of nonspecific gastrointestinal symptoms. Antacids react with hydrochloric acid to form salt and water, thereby neutralizing gastric acid and raising gastric pH.
It has also been known to combine a histamine H2-receptor antagonist and an antacid in a single solid dosage form in order to provide immediate relief of pain and discomfort by neutralization of gastric acid with the antacid and independent inhibition of acid secretion with the histamine H2-receptor antagonist. However, it is well known that when histamine H2-receptor antagonists are co-administered with antacids, a substantial reduction in plasma bioavailability of the histamine H2-receptor antagonist is frequently observed. Accordingly, combinations of a histamine H2-receptor and an antacid have been contraindicated.
U.S. Pat. Nos. 5,629,026 and 5,656,652 state that absorption of the histamine H2-receptor antagonist of a solid dosage form containing a histamine H2-receptor antagonist and an antacid may be enhanced by optimally buffering the composition to confer a pH substantially equal to that of the pKa of the histamine H2-receptor antagonist. These patents disclose tablet formulations prepared by blending antacid granules and a histamine H2-receptor antagonist, along with conventional tableting aids, fillers and palatability aids, and tableting on a conventional machine. These patents do not suggest any interaction between the antacid and the histamine H2-receptor antagonist, and do not suggest any need for separating the antacid from the histamine H2-receptor antagonist.
It has been determined that unless special precautions are taken, the histamine H2-receptor antagonist will degrade in the presence of an antacid. U.S. Pat. No. 5,817,340 discloses that degradation of the histamine H2-receptor antagonist can be prevented by interposing a film-forming polymer barrier between the histamine H2-receptor antagonist and the antacid to prevent the therapeutic ingredients from contacting each other. A first of the disclosed embodiments is a tri-layer tablet which includes a first layer containing an antacid, a second layer containing a histamine H2-receptor antagonist, and a barrier layer interposed between the first and second layers. The barrier layer is a film or diaphragm or membrane composed of plastic material which prevents migration of the antacid from the first layer to the second layer, and prevents migration of the histamine H2-receptor antagonist from the second layer to the first layer. An alternative embodiment comprises a core containing a first active ingredient (e.g., the antacid), a polymer barrier coated over the core, and a shell formed over the polymer coated core and containing a second active ingredient (e.g., the histamine H2-receptor antagonist). In another embodiment, granules comprising one of the active ingredients (e.g., the histamine H2-receptor antagonist) are coated with a polymer barrier, and the coated granules are then mixed with the second active ingredient (e.g., the antacid), and pressed into tablets.
Thus, the known orally administrable solid dosage forms containing both an antacid and a histamine H2-receptor antagonist are either prepared without any regard for degradation of the histamine H2-receptor antagonist due to contact with the antacid, or are prepared with a barrier layer between a first portion containing the antacid, and a second portion containing the histamine H2-receptor antagonist.
This invention is directed to a solid orally administrable pharmaceutical dosage form comprising a first portion including a therapeutically effective amount of a histamine receptor antagonist, and a second portion immediately adjacent the first portion without an intervening barrier layer, the second portion including a therapeutically effective amount of an antacid. More specifically, it has been discovered that the histamine H2-receptor antagonist can be stabilized and protected from degradation induced by contact with the antacid by physically separating the actives into different portions without a discrete barrier layer interposed between the portions.